Failure to achieve local and regional tumor control with radiation therapy remains a significant problem for a number of anatomic sites and can have a negative impact upon survival. There is emerging clinical and laboratory evidence that proliferation of tumor clonogens during the course of radiation treatment significantly impairs such local control. Recent in situ studies suggest that as many as half of all human carcinomas have the potential to double their cell number in five or fewer days. Thus, cells that survive the initial treatments might rapidly repopulate a tumor, leading to poorer control. The proposed Program will evaluate potential strategies for overcoming the negative impact of rapid proliferation in these cancers. The five coordinated Projects will evaluate three potential treatment strategies for dealing with proliferation: altered fractionation, use of S-phase specific radiosensitizers, and the use of biological and/or pharmacological modifiers that slow or inhibit cell division. Project I will investigate the effects of cytostatic drugs and biologicals on radiation damage and repair in primary human normal and malignant breast and prostate epithelial cells. Project II will examine halogenated pyrimidine metabolism in human tumor cell lines and xenografts with the goal of optimizing radiosensitization and evaluating mechanisms of modulating cell kinetics to enhance the proportion of tumor cells sensitized. The influence of antiestrogen treatment on the radiation response of MCF-7 human breast carcinoma xenografts will be investigated in Project III with an emphasis on treatment outcome, the emergence of hormone resistant tumors and the response of MCF-7 xenografts to fractionated radiotherapy in the absence of proliferation. Project IV consists of state-of-the art computer analysis of published and emerging clinical results in radiotherapy, from which rates of proliferation in tumors and/or radiosensitivity factors will be derived. The same programs will model results using parameters obtained from all other Projects, including clinical measurements from Project V to help in design of both laboratory experiments and clinical protocols. Project V will seek to establish correlations between tumor kinetics and local control rates, and initiate clinical trials designed to modify tumor cell proliferation and/or radiosensitivity via kinetic-specific treatment modifications including the use of halogenated pyrimidine analogs, accelerated fractionation or cytostatic therapy.